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Unformatted text preview: of Na+ channel showing how four domains are actually arranged around a central pore. 3 The liner arrangement of the segments is shown in the middle panel of Fig. 2. Each segment in a domain is linked to its neighboring segment by an intra or extracellular linker of hydrophilic amino acids. In addition each of the four domains is separated from its neighboring domain by a short intracellular hydrophilic segment. Notice that the hydrophilic stretches of amino acids are not embedded in the membrane but rather are in the extracellular or intracellular fluids and link the transmembrane segments. The arrangement of the segments and domains is not stretched out linearly in the membrane. Rather the four domains are folded, each next to its neighbor, to form a circular ring with a central pore. This arrangement would be seen if you could look down on the channel from the extraceullar space, as shown in the bottom panel of Fig. 2. In short, the sodium channel is a single, large protein composed of four domains, where each domain is, in turn, composed of 6 transmembrane segments. The transmembrane segments, together with the intracellular and extracellular linking segments, the hydrophilic linking regions, play specific roles in the channel operation. The above section showed the molecular arrangement of the Na+ channel. Another important channel that conducts cations is the calcium channel, which has not been discussed so far in the course but is exceptionally important and will be considered later in the course. The only point I wish to make here is that the structure of the calcium channel is strikingly similar to that of the Na+ channel (Fig. 3). It too is constructed from a single protein, has four domains each with six transmembrane segments. Figure. 3. Molecular structures of Na+ and Ca++ channels are similar. In the sections below we consider three features of the various segments; 1) which segment "senses" voltage (charge on the inside of the cell) and how that segment responds to membrane depolarization to open activation gates; 2) which portions form the inactivation gate and how the inactivation gate is coupled to the voltage sensor; 3) the pore region through which the ions travel and how the structure of the pore region 4 confers exquisite selectivity for one particular ion and excludes other ions. As a preview, the S4 segment is the voltage sensor, the intracellular linkage region between segments III and IV form the inactivation gate, and segments S56 form the pore. We first consider the voltage sensor in S4 and then turn to the inactivation gate. In the final portion we consider the ion selectivity filter in the pore, which is one of the great stories in molecular neurobiology. The S4 segment is the voltage sensor and opens the activation gate For an ion channel to respond to changes in the electric charge across the membrane, some charged part of it must act as a voltage sensor and must undergo some movement that triggers the opening of the activation gate. This idea was originally postulated by Hodgkin and Huxley in 1952. They proposed that the gating of a channel was accompanied by movement of a charge within the membrane. Such a movement of charge within the protein constitutes a small current, which is now called the gating current (Fig. 5). It should be noted that the gating current is very small because it is only due to the small movement of a charged element of the protein and it occurs before the channel actually opens, which then allows a much larger current, carried by Na+ ions, to flow through the pore of the channel. The S4 segment has the exact properties required for a voltage sensor. In the S4 segment, basic (positively charged) amino acids occur at every third residue and form a spiral of positive charge on the outside of an helical segment (an helix makes a complete turn for each 3.4 amino acids). In the S4 transmembrane segment, each of these positive charges is paired to negative charges in the helices of neighboring segments, thereby helping to stabilize the segment or helix (Fig.4). The positive charges on the outside of the...
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This note was uploaded on 09/17/2009 for the course BIO 365R taught by Professor Draper during the Spring '08 term at University of Texas at Austin.
- Spring '08